Emerging evidence highlights the potential role of cardiac mitochondria as central regulators of excitability and arrhythmias. In recent years, mitochondria have been increasingly recognized as highly dynamic organelles that fuse and divide. These morphological changes, caused by complex fusion and fission events, are essential for embryonic development, neuronal plasticity, apoptosis, and calcium signaling. Disruption of the balance between mitochondrial fusion and fission results in either highly interconnected mitochondrial networks (favoring fusion) or abnormally fragmented mitochondria (favoring fission). Our fundamental understanding of these opposing processes was recently advanced by the identification of key proteins that regulate mitochondrial dynamics. Of particular interest to this R21 proposal is the dynamin related protein (DRP1), a member of the conserved dynamin GTPase superfamily, which controls mitochondrial fission in most cell types, including cardiomyocytes. The functional importance of DRP1 is underscored by the fact that overexpression of DRP1 resulting in fragmented mitochondria promotes cell death whereas silencing or chemical inhibition of DRP1 attenuates this process. To date, the role of DRP1 in the pathogenesis of cardiovascular disorders has received very little attention. Despite recent findings that mechanistically link mitochondrial fission to apoptosis, the potential implications o altered DRP1 expression/function for modulating arrhythmia susceptibility remain completely unknown. The central tenant of this R21 proposal is that DRP1 mediated regulation of mitochondrial fission is a major determinant of arrhythmogenesis. In this project we will use pharmacological and gene based approaches to modulate the function and expression of DRP1 in the heart. We will determine if altered mitochondrial morphometry/structure modulates the genesis of arrhythmias under acute (Aim 1) and chronic (Aim 2) oxidative stresses. Completion of these studies will reveal a potentially novel mitochondrial target for arrhythmia prevention.